Polymorphic form of a long-acting beta-2 adrenoceptor agonist

Abstract

New polymorphic form of a long-acting beta-2 adrenoceptor agonist A new polymorphic form of arformoterol tartrate, designated as form D, is provided and which is characterized by at least one of the following: (i) a powder X-ray diffraction pattern having peaks at approximately 6.8, 13.3, 13.6, 3.8, 14.1, 18.2, 18.7, 20.0±0.2 degrees two theta; or (ii) a DSC thermogram showing an endothermic peak with an onset at approximately 19-120° C., and a maximum at approximately 129-131° C., followed by an exothermic peak with a maximum at approximately 137-138° C.; wherein the DSC thermogram of form D has a further endothermic peak with an onset at approximately 168-170° C.1 Processes for preparing the new polymorphic form, uses thereof and intermediates for the preparation thereof, are also provided.

The invention claimed is: 
     
       1. A polymorphic form of arformoterol tartrate, designated as form D, which is characterized by at least one of the following:
 (i) a powder X-ray diffraction pattern having peaks at 6.8, 13.3, 13.6, 13.8, 14.1, 18.2, 18.7, 20.0±0.2 degrees two theta; or 
 (ii) a DSC thermogram showing an endothermic peak with an onset at approximately 119-120° C., and a maximum at approximately 129-131° C., followed by an exothermic peak with a maximum at approximately 137-138° C.; wherein the DSC thermogram of form D has a further endothermic peak with an onset at approximately 168-170° C. 
 
     
     
       2. The polymorphic form of arformoterol tartrate form D according to  claim 1 , which has a powder X-ray diffraction pattern further comprising one or more additional peaks at 7.4, 15.9, 25.1 and 25.8±0.2 degrees two theta. 
     
     
       3. The polymorphic form of arformoterol tartrate form D according to  claim 1 , having a powder X-ray diffraction pattern in accordance with  FIG. 1 . 
     
     
       4. A mixture of form D and polymorph A of arformoterol tartrate, having at least 30% (w/w) of form D. 
     
     
       5. The mixture of form D and polymorph A according to  claim 4 , having between 40 and 50% of the known polymorph A. 
     
     
       6. A process for preparing arformoterol tartrate form D from arformoterol base, the process comprising the steps of:
 a) providing a mixture of arformoterol base with an alcohol, or with a combination of acetonitrile and an alcohol, at a temperature between 15 and 60° C.; 
 b) adding a solution of L-tartaric acid in a solvent selected from an alcohol, water and mixtures thereof, to the mixture obtained in step (a); 
 c) cooling the mixture of step (b) to a temperature between 30 and 15° C., when necessary, followed by stirring to obtain a solid; 
 d) further cooling the mixture of step (c) to a temperature between 0 and 10° C.; and 
 e) collecting the crystals obtained in step (d), and drying the crystals under inlet air pressure and at a temperature between 30 and 50° C. to yield arformoterol tartrate form D. 
 
     
     
       7. The process according to the  claim 6 , wherein the mixture provided in step (a) is a mixture of arformoterol base with an alcohol, selected from methanol, ethanol, or isopropanol; preferably methanol or ethanol; more preferably methanol. 
     
     
       8. The process according to  claim 6 , wherein the solution used in step (b) is a solution of L-tartaric acid in an alcohol, selected from methanol, ethanol, or isopropanol; preferably methanol or ethanol; more preferably methanol. 
     
     
       9. The process according to the  claim 6 , wherein the alcohol used in steps (a) and (b) is the same and is selected from methanol, ethanol and isopropanol. 
     
     
       10. The process according to  claim 9 , wherein the preferred alcohol used in step (a) and/or step (b) is methanol or ethanol. 
     
     
       11. The process according to  claim 6 , wherein the ratio of the alcohol/acetonitrile used in step (a) is of at least 1:0.1, preferably between 1:1 and 1:5. 
     
     
       12. The process according to  claim 6 , wherein the mixture of step (a) is preferably at a temperature between 20 and 60° C. 
     
     
       13. The process according to  claim 6 , wherein the temperature of the cooling carried out in step (d) is preferably between 0 and 5° C. 
     
     
       14. A process for the preparation of a mixture of form D and polymorph A of arformoterol tartrate, optionally from other polymorphic forms of arformoterol tartrate, and comprising the steps of:
 a) providing a mixture of arformoterol tartrate and a solvent which is a mixture of an alcohol and water, at a temperature between 60 and 70° C.; 
 b) cooling the mixture obtained in step (a) to a temperature between 50 and 55° C.; 
 c) adding acetonitrile to the mixture obtained in step (b) until a suspension is obtained; 
 d) cooling the suspension obtained in step (c) while stirring to a temperature between 10 and 30° C. to obtain a solid; and 
 e) collecting the crystals obtained in step (d) and drying the crystals under vacuum at a pressure between 0.75 and 40 mm Hg and at a temperature between 50 and 90° C.; 
 wherein the ratio of alcohol:water used in step (a) is over 1:1 and up to 5:1, wherein the mixture of form D and polymorph A of arformoterol tartrate so prepared is according to  claim 4 . 
 
     
     
       15. A pharmaceutical composition comprising the arformoterol tartrate according to  claim 1  and at least one pharmaceutically acceptable excipient or carrier. 
     
     
       16. A method of effecting bronchodilation, the method comprising the administration, to a subject in need of such treatment, of a therapeutically effective amount of arformoterol tartrate according to  claim 1 . 
     
     
       17. A method of effecting bronchodilation, the method comprising the administration, to a subject in need of such treatment, of a pharmaceutical composition according to  claim 15 . 
     
     
       18. The mixture of form D and polymorph A according to  claim 4  having from 40% to 90% (w/w) of polymorphic form of arformoterol tartrate form D relative to the total weight of form D and polymorph A. 
     
     
       19. The mixture of form D and polymorph A according to  claim 5  having from 50% to 80% (w/w) of polymorphic form of arformoterol tartrate form D relative to the total weight of form D and polymorph A.